title: A phase 1 dose-escalation study of irinotecan in combination with 17-allylamino-17-demethoxygeldanamycin in patients with solid tumors.
abstract: OBJECTIVE
  Both heat shock protein 90 (Hsp90) and checkpoint kinase 1 (Chk1) have emerged as novel therapeutic targets. We conducted a phase I study of irinotecan and the Hsp90 inhibitor 17AAG, which can also down-regulate Chk1, in patients with solid tumors.
  
  
  METHODS
  During the dose escalation phase, patients received i.v. irinotecan followed by 17AAG once weekly for 2 weeks in a 21-day cycle. At the maximum tolerated dose (MTD), additional patients were enrolled to undergo pre- and post-17AAG tumor biopsies for pharmacodynamic evaluation. The pharmacokinetics of irinotecan, 17AAG, and their metabolites were characterized. Tumor p53 status as determined by immunohistochemistry was correlated with antitumor activity.
  
  
  RESULTS
  Twenty-seven patients with a variety of solid tumors were enrolled. Four patients developed dose-limiting toxicity at dose level 4 (100 mg/m(2) irinotecan and 375 mg/m(2) 17AAG) including nausea, vomiting, diarrhea, and pulmonary embolism. The pharmacokinetics of 17AAG and its metabolite were not significantly affected by the coadministration of irinotecan, and vice versa. There was no partial response, although tumor shrinkage was observed in six patients. Five of 10 patients with p53-mutant tumor had stable disease as the best response compared with 2 of 6 patients with p53-wildtype tumor (P = 0.63). Evidence for Hsp90 inhibition by 17AAG, resulting in phospho-Chk1 loss, abrogation of the G(2)-M cell cycle checkpoint, and cell death could be shown in tumor biopsy samples obtained at the MTD.
  
  
  CONCLUSIONS
  The combination of irinotecan and 17AAG can be given to patients with acceptable toxicity. The recommended phase II dose of the combination is 100 mg/m(2) irinotecan and 300 mg/m(2) 17AAG.
authors.affiliation: Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA. tsea@mskcc.org
authors.forename: Archie N
authors.initials: AN
authors.lastname: Tse
authors.forename: David S
authors.initials: DS
authors.lastname: Klimstra
authors.forename: Mithat
authors.initials: M
authors.lastname: Gonen
authors.forename: Manish
authors.initials: M
authors.lastname: Shah
authors.forename: Tahir
authors.initials: T
authors.lastname: Sheikh
authors.forename: Rachel
authors.initials: R
authors.lastname: Sikorski
authors.forename: Richard
authors.initials: R
authors.lastname: Carvajal
authors.forename: Janet
authors.initials: J
authors.lastname: Mui
authors.forename: Caroll
authors.initials: C
authors.lastname: Tipian
authors.forename: Eileen
authors.initials: E
authors.lastname: O'Reilly
authors.forename: Ki
authors.initials: K
authors.lastname: Chung
authors.forename: Robert
authors.initials: R
authors.lastname: Maki
authors.forename: Robert
authors.initials: R
authors.lastname: Lefkowitz
authors.forename: Karen
authors.initials: K
authors.lastname: Brown
authors.forename: Katia
authors.initials: K
authors.lastname: Manova-Todorova
authors.forename: Nian
authors.initials: N
authors.lastname: Wu
authors.forename: Merrill J
authors.initials: MJ
authors.lastname: Egorin
authors.forename: David
authors.initials: D
authors.lastname: Kelsen
authors.forename: Gary K
authors.initials: GK
authors.lastname: Schwartz
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D016227:Benzoquinones / Q000008:administration & dosage; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors; D006801:Humans; D000077146:Irinotecan; D047029:Lactams, Macrocyclic / Q000008:administration & dosage; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy*; D016896:Treatment Outcome
chemical_list: D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; C112765:tanespimycin; D000077146:Irinotecan; D002166:Camptothecin